Preserved vascular integrity and enhanced survival following neuropilin-1 inhibition in a mouse model of CD8 T cell-initiated CNS vascular permeability
- Equal contributors
1 Neuroscience Graduate Program, University of Cincinnati, Cincinnati, OH, 45267, USA
2 Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
3 Department of Neuroscience, Mayo Clinic, Rochester, MN, 55905, USA
4 Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA
5 Department of Immunology, Mayo Clinic, Gugenheim Building 4-11C, 200 First St. SW, Rochester, MN, 55905, USA
Journal of Neuroinflammation 2012, 9:218 doi:10.1186/1742-2094-9-218Published: 18 September 2012
Altered permeability of the blood–brain barrier (BBB) is a feature of numerous neurological conditions including multiple sclerosis, cerebral malaria, viral hemorrhagic fevers and acute hemorrhagic leukoencephalitis. Our laboratory has developed a murine model of CD8 T cell-initiated central nervous system (CNS) vascular permeability in which vascular endothelial growth factor (VEGF) signaling plays a prominent role in BBB disruption.
In this study, we addressed the hypothesis that in vivo blockade of VEGF signal transduction through administration of peptide (ATWLPPR) to inhibit neuropilin-1 (NRP-1) would have a therapeutic effect following induction of CD8 T cell-initiated BBB disruption. We report that inhibition of NRP-1, a co-receptor that enhances VEGFR2 (flk-1) receptor activation, decreases vascular permeability, brain hemorrhage, and mortality in this model of CD8 T cell-initiated BBB disruption. We also examine the expression pattern of VEGFR2 (flk-1) and VEGFR1 (flt-1) mRNA expression during a time course of this condition. We find that viral infection of the brain leads to increased expression of flk-1 mRNA. In addition, flk-1 and flt-1 expression levels decrease in the striatum and hippocampus in later time points following induction of CD8 T cell-mediated BBB disruption.
This study demonstrates that NRP-1 is a potential therapeutic target in neuro-inflammatory diseases involving BBB disruption and brain hemorrhage. Additionally, the reduction in VEGF receptors subsequent to BBB disruption could be involved in compensatory negative feedback as an attempt to reduce vascular permeability.